A series of anti-HIV nucleoside conjugates of ether and thioether phospholipids will be synthesized in an attempt to improve therapeutic indices of the parent drugs. Since the proposed prodrugs are conjugates of two biologically active moieties (nucleoside and ether lipid), the improved therapeutic effects would be expected upon the release of two moieties and their metabolites by hydrolysis of the phosphate bond as demonstrated previously with the antitumor nucleoside conjugates. It is anticipated that the proposed conjugates will enhance the activity of the anti-HIV nucleosides by 1) potential targeting to macrophage reservoir of HIV infection, thereby reducing the toxicity of the nucleosides to other cells by micellar formulation, 2) sustained release of the nucleosides, 3) combination with a biological response modifier (ether and thioether lipids), 4) increased lipophilicity of the nucleosides, and 5) possible inhibition of CD4 glycoprotein synthesis by the phosphatidic acid released from the conjugate. The specific aims are 1) synthesis of nucleoside 5'-diphosphate-rac-1-0- (or-S-) tetradecyl (or octadecyl)-2-0-palmitoyl-glycerols (or 1- thioglycerols); the nucleosides include 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine, 3'-azido-2',3'-dideoxyuridine (SC-87), 2',3'- dideoxyadenosine, and 2',3'-dideoxy-N6-methyladenosine and formulation of micelle-solubilized anti-HIV agents using sonicated solution of the proposed conjugates in which the anti-HIV agents include AL-721, rifabutin, and amphotericin B methyl ester. The conjugates will be synthesized by condensation of the nucleoside 5'- monophosphoromorpholidate and the 1-0-(or-S-) alkyl glycerol (or- thioglycerol) 3-phosphate. The latter will be prepared chemically from glycerol or 1-thioglycerol. The conjugate will be purified by a DE-52 (AcO-) cellulose ion exchange column chromatography using a linear gradient of 0-0.15 M ammonum acetate in CHC13-CH3OH-H2O (2:3:1). The conjugates will be formulated as a micellar solution (size 0.01-0.1 mum) by sonication of water suspension of the conjugate. The micellar solution also dissolves the water-insoluble anti-HIV agents. The proposed conjugates and the micelle-solubilized drug formulation will be sent to the National Institute of Allergy and Infectious Diseases for screening of anti-HIV activity.